P53

p53 Tumor Suppressor Protein

The name p53 refers to its apparent molecular mass. It runs as a 53 kDa molecule on SDS-PAGE. But based on calculations from its amino acid residues, p53's mass is actually 43.7 kDa. This difference may be due to the high number of proline residues in the protein, resulting in its migrating slowly on SDS-PAGE.

Human p53 is 393 amino acids long and has seven domains:

- Transcription activation domain

- Activation domain 2

- Proline rich domain

- DNA-binding core domain

- A nuclear localization signaling domain

- Tetramerizatin domain

- C-theminal domain

p53 tumor suppressor is a flexible molecule composed of four identical protein chains. Flexible molecules are difficult to study by x-ray crystallography because they do not form orderly crystals. So p53 has been studied in parts, by removing the flexible regions and solving structures of the pieces that form stable structures. The figure at the right shows the cartoon representation of the DNA-binding domain, which has been studied most.



p53 Pathway and Mutation

In a normal cell, p53 is inactivated by its negative regulatory mdm2 (hdm2 in humans) and it is found at low levels. When DNA damage is sensed, p53's level rises. p53 binds to many regulatory sites in the genome and begins production of proteins that stop cell division until the damage is repaired. If the damage is irreparable, p53 initiates the process called programmed cell death, apoptosis, permanently removing the damage.

In most cases of human cancer, p53 mutations have been observed. Most of the p53 mutations that may result in cancer are found in and around the DNA-binding surface of the protein. The most common mutation changes R248, an amino acid that interacts with DNA. When mutated to another amino acid, this interaction is lost. Other residues associated with cancer-causing mutations are arginine 175, 249, 273, 282 and glycine 245. The figure at the right shows interaction of the DNA-binding domain with DNA. Key residues associated with mutations are represented by spheres.



Surface charge of the DNA binding domain

The figure at the left shows the surface charge of the p53 DNA-binding domain. It is rich in arginine amino acids that interact with DNA, and this causes its surface to be positively charged. This domain recognizes specific regulatory sites on the DNA. The flexible structure of p53 allows it to bind to many different variants of binding sites, allowing it to regulate transcription at many places in the genome.



Click Here to view a Three-dimensional Representation of the DNA-binding Domain Bound to DNA

There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues C176, H179, C238, and C242 that are located on two loops, respectively. It is conceivable that the zinc plays a role in stabilizing the two loops through coordination. The Zn has been represented as a red sphere in the figure at the right.

Additional Resources
For additional information, see: Cancer

For additional information, see: Oncogenes